The phosphodiesterases (PDEs) are a superfamily of enzymes with eleven members encoded by 21 genes that regulate intracellular cyclic nucleotide signaling (i.e., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)). The PDEs contain a variable N-terminal regulatory domain and a highly conserved C-terminal catalytic domain and differ in their substrate specificity, expression and localization in cellular and tissue compartments, including the CNS. In neurons these cyclic nucleotides serve as second messengers in the signaling cascade of G-protein coupled receptors and lead to the activation of kinases which, in turn, will phosphorylate proteins involved in the regulation of synaptic transmission and homeostasis.
The PDE9 enzyme selectively hydrolyzes cGMP over cAMP and has the highest affinity of any PDE for cGMP, Km ˜170 nM (Fisher et al., Journal of Biological Chemistry 1998, 273 (25), 15559-15564). PDE9 is found to be present in a variety of human tissues including prostate, colon, small intestine, spleen, kidney, brain and skeletal muscle. Specifically, PDE9 mRNA is found in the hippocampal formation further suggesting a role in learning and memory. Studies have also implicated cGMP pathways in synaptic plasticity. In PDE9 knockout mice, long term potentiation (LTP) is enhanced suggesting that PDE9 inhibition can improve learning and memory. Indeed, a selective PDE9 inhibitor was shown to potentiate LTP at the Schaeffer collateral/CA1 synapse, a region of the hippocampus known to be involved in learning and memory (Van der Staay et al., Neuropharmacology, 2008, 55 (5), 908-918; Huttson et al., Neuropharmacology, 2011, 61 (4), 665-676). In multiple studies, selective PDE9 inhibitors were effective in attenuating the deficits observed in passive avoidance, novel object recognition, social recognition, and T-maze behavioral assays (Van der Staay et al., Neuropharmacology, 2008, 55 (5), 908-918). Furthermore, in two studies, neurite outgrowth, a measure of synaptic plasticity, was increased following PDE9 inhibition (Huttson et al., Neuropharmacology, 2011, 61 (4), 665-676; Menitti, ICAD, 2009). Overall the data suggest that modulation of neuronal cGMP via inhibition of PDE9 can alter synaptic processes including learning and memory.
As such, there remains a strong need for novel PDE9 inhibitors for use in increasing synaptic plasticity and synaptic processes, for example, involved in learning, memory, as well as CNS diseases or disorders related to modulation of cGMP levels.